Contrave is started at a low dose and gradually increased. A total daily dosage of two Contrave 8 mg/90 mg tablets twice daily (32 mg/360 mg) is reached at the start of Week 4. Contrave may interact with monoamine oxidase inhibitors (MAOIs), opioid-containing medicines (such as cough and cold remedies, antidiarrheal drugs, and opioid analgesics), antidepressants, antipsychotics, beta-blockers, antiarrhythmics, ticlopidine, clopidogrel, ritonavir, lopinavir, efavirenz, theophylline, corticosteroids, levodopa, amantadine, and alcohol. Tell your doctor all medications and supplements you use. Contrave is not recommended for use during pregnancy. It may harm a fetus. This drug passes into breast milk and is not recommended for use while breastfeeding. Withdrawal symptoms may occur if you suddenly stop taking this medication.

Our Contrave (naltrexone HCl and bupropion HCl) Extended-release Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, the adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.

CONTRAVE was evaluated for safety in five double-blind
placebo controlled trials in 4,754 overweight or obese patients (3,239 patients
treated with CONTRAVE and 1,515 patients treated with placebo) for a treatment
period up to 56 weeks. The majority of patients were treated with CONTRAVE 32
mg/360 mg total daily dose. In addition, some patients were treated with other
combination daily doses including naltrexone up to 50 mg and bupropion up to
400 mg. All subjects received study drug in addition to diet and exercise
counseling. One trial (N=793) evaluated patients participating in an intensive
behavioral modification program and another trial (N= 505) evaluated patients
with type 2 diabetes. In these randomized, placebo-controlled trials, 2,545
patients received CONTRAVE 32 mg/360 mg for a mean treatment duration of 36
weeks (median, 56 weeks). Baseline patient characteristics included a mean age
of 46 years, 82% women, 78% white, 25% with hypertension, 13% with type 2 diabetes,
56% with dyslipidemia, 25% with BMI greater than 40 kg/m², and less than 2%
with coronary artery disease. Dosing was initiated and increased weekly to
reach the maintenance dose within 4 weeks.

In CONTRAVE clinical trials, 24% of subjects receiving
CONTRAVE and 12% of subjects receiving placebo discontinued treatment because
of an adverse event. The most frequent adverse reactions leading to
discontinuation with CONTRAVE were nausea (6.3%), headache (1.7%) and vomiting
(1.1%).

Common Adverse Reactions

Adverse reactions that were reported by greater than or
equal to 2% of patients, and were more frequently reported by patients treated
with CONTRAVE compared to placebo, are summarized in Table 3.

Table 3: Adverse Reactions Reported by Obese or
Overweight Patients With an Incidence (%) of at Least 2% Among Patients Treated
with CONTRAVE and More Common than with Placebo

Psychiatric And Sleep Disorders

In the one-year controlled trials of CONTRAVE, the proportion
of patients reporting one or more adverse reactions related to psychiatric and
sleep disorders was higher in the CONTRAVE 32/360 mg group than the placebo
group (22.2% and 15.5%, respectively). These events were further categorized
into sleep disorders (13.8% CONTRAVE, 8.4% placebo), depression (6.3% CONTRAVE,
5.9% placebo), and anxiety (6.1% CONTRAVE, 4.4% placebo). Patients who were 65
years or older experienced more psychiatric and sleep disorder adverse
reactions in the CONTRAVE group (28.6%) compared to placebo (6.3%), although
the sample size in this subgroup was small (56 CONTRAVE, 32 placebo); the
majority of these events were insomnia (10.7% CONTRAVE, 3.1% placebo) and
depression (7.1% CONTRAVE, 3.1% placebo).

Neurocognitive Adverse Reactions

Adverse reactions involving attention, dizziness, and
syncope occurred more often in individuals randomized to CONTRAVE 32/360 mg
group compared to placebo (15.0% and 5.5%, respectively). The most common
cognitive-related adverse reactions were attention disorders (2.5% CONTRAVE,
0.6% placebo). Adverse reactions involving dizziness and syncope were more
common in patients treated with CONTRAVE (10.6%) than in placebo-treated
patients (3.6%); dizziness accounted for almost all of these reported events (10.4%
CONTRAVE, 3.4% placebo). Dizziness was the primary reason for discontinuation
for 0.9% and 0.3% of patients in the CONTRAVE and placebo groups, respectively.

Increases In Serum Creatinine

In the one-year controlled trials of CONTRAVE, larger
mean increases in serum creatinine from baseline to trial endpoint were
observed in the CONTRAVE group compared with the placebo group (0.07 mg/dL and
0.01 mg/dL, respectively) as well as from baseline to the maximum value during
follow-up (0.15 mg/dL and 0.07 mg/dL, respectively). Increases in serum
creatinine that exceeded the upper limit of normal and were also greater than
or equal to 50% higher than baseline occurred in 0.6% of subjects receiving
CONTRAVE compared to 0.1% receiving placebo. An in vitro drug-drug interaction
study demonstrated that bupropion and its metabolites inhibit organic cation
transporter 2 (OCT2), which is involved in the tubular secretion of creatinine,
suggesting that the observed increase in serum creatinine may be the result of
OCT2 inhibition.

Based on in vitro results and FDA guidance for Drug
Interaction Studies, the ratios of the free (unbound) Cmax and IC50 value of
bupropion and hydroxybupropion were well below 0.1 suggesting a drug-drug
interaction between CONTRAVE and OCT2 substrate due to bupropion and
hydroxybupropion is unlikely. The ratio for the threohydrobupropion and
erythrohydrobupropion metabolite mixture was 0.29, suggesting a drug-drug
interaction between CONTRAVE and OCT2 due to threohydrobupropion and
erythrohydrobupropion is possible.

Postmarketing Experience

Additional adverse reactions have been identified during
post approval use of CONTRAVE. Because these reactions are reported voluntarily
from a population of uncertain size, it is generally not possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.